Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune-related adverse event reveal upregulation of toll-like receptor 4/complement-induced innate immune response and increased density of T

Publication Title

Journal of cutaneous pathology

Authors

Mario L Marques-Piubelli
Riyad N H Seervai, Internal Medicine Residency Program, Providence Portland Medical Center, Portland, Oregon, USAFollow
Kumaran M Mudaliar
Wencai Ma
Denái R Milton
Jing Wang
Aaron Muhlbauer
Edwin R Parra
Luisa M Solis
Priyadharsini Nagarajan
Jodi Speiser
Courtney Hudgens
Woo Cheal Cho
Phyu P Aung
Anisha Patel
Omar Pacha
Kelly C Nelson
Michael T Tetzlaff
Rodabe N Amaria
Carlos A Torres-Cabala
Victor G Prieto
Ignacio I Wistuba
Jonathan L Curry

Document Type

Article

Publication Date

7-1-2023

Keywords

oregon; portland; ppmc; genomics

Abstract

Background: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology.

Methods: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH 1) cells (Tbet), TH 2 cells (Gata3), TH 17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis.

Results: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH 2, TH 17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH 1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples.

Conclusions: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH 1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.

Keywords: bullous pemphigoid-irAE; gene expression profiling; immune mechanisms; multiplex immunofluorescence.

Specialty/Research Institute

Dermatology